Low crystallinity cellulose excipients

ABSTRACT

A rapid method to prepare low crystallinity cellulose (crystallinity 15-45% of polymerization 35-150), suitable for use as a direct compression excipient (e.g., binder, disintegrant, and diluent) in pharmaceutical solid dosage forms design and as a bodying and/or film forming agent in the development of sustained- and/or film forming agent in the development of sustained- and/or controlled-release pharmaceutical (topical and transdermal products), cosmetics, agricultural, personal care and like products, is provided by reacting cellulose materials with 85% or higher weight percentage phosphoric acid under controlled sequenced temperature conditions that involve treatment first at room temperature for an hour and then at 50°-55° C. for 3-6 hours, followed by separating by a precipitation method,. and subsequently isolating as a powder or converting into a head or hydrated form.

This is a divisional of application Ser. No. 07/990,621 filed on Dec.14, 1992, now U.S. Pat. No. 5,417,984.

BACKGROUND OF THE INVENTION

Cellulose is the most abundant natural polymer. All forms of plant lifecontain cellulose. Because of its nearly ubiquitous distribution innature, and human kinds' long exposure to cellulose, cellulose and itsderivatives are generally recognized as the safest and most acceptablepolymer class for use in food and pharmaceutical products. In itsnaturally occurring form, cellulose exists as a fibrous structurecomposed of arrays of long chains of cellulose molecules held togetherby van der Waal forces and interchain hydrogen bonds. The chemicalstructure of cellulose consists of repeating units of β-D glucopyranoserings linked together by β-1,4-glycosidic linkages. Depending on thedegrees of order of arrangement and hydrogen bonding between cellulosechains, the crystallinity of the cellulose may range from 50% to 90%.The crystallinity of native cellulose is about 70% (P. H. Hermans and A.Weidinger, J. Poly. Sci., IV, 135,(1949)). The amorphous regions in thestructure can result from damage during processing of pulp, fromdifferent chain bonding order (i.e., occurrence of β-1, 6-linkageinstead of the regular β-1,4-glycosidic bond) or as a result of naturalimperfections. The degree of polymerization of cellulose may range from1,000 to 10,000, depending on its source.

The reactions of cellulose with mineral acids to prepare non-fibrous,low molecular weight (i.e., low degree of polymerization) celluloseproducts suitable for use in food, cosmetics, pharmaceutical, and likeproducts, have been extensively studied. The reactivity of cellulosetowards acids depends on the crystallinity of the cellulose source, acidconcentration, and the reaction temperature and duration. Severalproducts with varying degrees of crystallinity and polymerization havebeen prepared. Battista (U.S. Pat. Nos. 2,978,446 and 3,146,170)disclose the preparation of level-off cellulose products suitable forthe manufacture of microcrystalline cellulose--the most commonly andwidely used direct compression excipient for pharmaceutical solid dosageform design, by reacting a cellulose material with 2.5N hydrochloricacid at boiling temperature for 15 minutes. According to the invention,the products produced are highly crystalline in nature. The level-offdegree of polymerization values of products prepared from native fibersrange between 200 and 300, whereas those prepared from regeneratedcellulose lie in the range of from 15 to 60, and products prepared fromalkali swollen natural forms of cellulose are in a degree ofpolymerization range between 60 and 125. Similar manufacturingprocedures, to that described above, are described in German Patent DAS1,123,460, using viscose cellulose as the starting cellulose source, andin Austrian Patent No. 288,805. The use of gaseous HCl, at temperaturesbelow 40° C., without solvent, to prepare the cellulose precursor formicrocrystalline cellulose, is disclosed in (East) German patent DD71,282.

Ellefsen et al., in Norsk Skog Industri, 1959, p. 411, describe thepreparation of crystalline cellulose products by dissolving the startingcellulose source in 38-40.3% concentrated hydrochloric acid at 20° C.,followed by precipitating with water. In U.S. Pat. No. 4,357,467, asimilar procedure to the foregoing, using 37-42% HCl acid at 30°-50° C.,is employed to prepare cellulose products having substantially reducedcrystallinity (17-83%), and a low degree of polymerization (10-200).Compared to native and regenerated cellulose, the low crystallinitycellulose products show improved dispersibility in water, increasedcompatibility with basic compounds such as starches, proteins, andlipids, and are useful as excipients in the preparation of tablets andconfectionery products.

Greidinger et al (U.S. Pat. No. 3,397,198) disclose the preparation ofan amorphous degraded cellulose by treating a cellulose material with65-75% sulfuric acid at a temperature of 35°-45° C. for a period of nolonger than 10 minutes. The amorphous product is suitable for use incleaners, cosmetic preparations, foodstuffs or as a filler for materialssuch as plaster-of-paris or adsorbents.

V. M. Brylyakove (SU Patent 4266981) describe the preparation ofmicrocrystalline cellulose utilizing 3-5% nitric acid, sulfuric acid orhydrochloric acid and a fatty acid (C₁₀₋₂₀) at 96°-98° C. The fatty acidenhances the efficiency of the process.

Other references that can be cited, pertinent to the preparation ofmicrocrystalline cellulose, are: CA 111 (8) 59855w; CA 111 (8) 59787a;CA 108 (18) 152420y; CA 104 (22) 188512m; CA 104 (24) 209374K; CA 104(24) 193881C; CA 99 (24) 196859y; CA 98 (12) 95486y; CA 94 (9) 64084d;and CA 85 (8) 48557u.

The interaction of cellulose with phosphoric acid has been the subjectof several publications. S. M. Hudson and J. A. Cuculo, Macromol. Sci.-Rev. Macromol. Chem., C18, 6-7 (1980) and J. O. Warwicker, in Celluloseand Cellulose Derivatives," N. M. Bikales and L. Segal, eds., Wiley, NewYork, N.Y. (1971), Vol. V, Part IV, p. 325-79, describe that theswelling and/or dissolution of cellulose in phosphoric acid depend(s) onthe concentration of the acid. In concentration range between 71-80%,the swelling of cellulose is rapid. Further increases in theconcentration causes dissolution of the cellulose. According to Hudsonand Cuculo, the dissolution of cellulose is incomplete when the acidsolution contains higher than 85% and less than 92% phosphoric acid. S.N. Danilov and N. F. Gintse, Zh. Obsch. Khim., 26, 3014 (1956), describethat the cellulose dissolves more readily with increasing temperature,with a maximum dissolution rate at 40°-50° C.

Bellamy and Holub (U.S. Pat. No. 4,058,411) disclose the use of 80-85%phosphoric acid for the decrystallization of cellulose. According to theinvention, the starting cellulose source, having particles about onemillimeter in length and diameter, is reacted with phosphoric acid atroom temperature, with or without the presence of a surfactant, for aprolonged period until a gel is formed. The product is then precipitatedfrom the gel using an aqueous solution of tetrahydrofuran. The amorphousproduct can be used as a source of glucose or as a substrate formicrobial production of antibiotics and other metabolites, single cellproteins and industrial alcohol.

In Swiss Patent No. 79,809, a method is described for thedepolymerization of cellulose using a mixture of hydrochloric acid andsulfuric acid or phosphoric acid (25-35%) at temperatures below 50° C.,is provided. There is, however, no mention of the crystallinity of theproduct in the disclosure.

We have found that the treatment of cellulose with phosphoric acid,under controlled sequenced temperature conditions, provides a rapidmethod of preparing low crystallinity cellulose products that aresuitable for use as excipients in cosmetic, food, pharmaceutical, andlike products.

Accordingly, the primary objective of this invention is to provide arapid method for converting fibrous cellulose material to useful lowcrystallinity cellulose excipients using phosphoric acid.

A further objective of the present invention is to provide new lowcrystallinity cellulose excipients suitable for use in cosmetic,pharmaceutical, personal care, and like products.

Still another objective of this invention is to provide a bodying agentand/or film forming agent composed of hydrated low crystallinitycellulose.

These and other objectives of the present invention will be moreapparent from the discussion that follows.

SUMMARY OF THE INVENTION

The present invention provides new low crystallinity cellulose (LCC)excipients, namely, low crystallinity powder cellulose (LCPC), lowcrystallinity bead cellulose (LCBC), and low crystallinity hydratedcellulose (LCHC), suitable for use in cosmetic, pharmaceutical, personalcare, and like products, prepared by reacting a cellulose material with80% or higher weight percentage phosphoric acid, (preferably 85% to 99%)first at room temperature (i.e. from 15° C. to 30° C.) for up to aboutan hour, and then at 50°-60° C. for a period of time (typically 3-6hours), sufficient to dissolve the cellulose in the acid. As usedherein, the term low crystallinity cellulose is intended to refer to awhite solid material that precipitates when water or an appropriateorganic solvent is combined with the above reaction solution, which canthen be readily isolated as a powder (LCPC), or converted into a beadform (LCBC) or into an aqueous colloidal dispersion (LCHC). The degreeof crystallinity of the products, prepared under the conditions of thisinvention, ranges between about 15% and 45%, and the degree ofpolymerization values range from about 35 to 150.

Therefore, the present invention also provides a rapid method wherebycellulosic materials, such as cotton linters, purified cotton papers,α-cellulose, purified wood pulp, microcrystalline cellulose, or likematerials, can be readily converted into a low crystallinity celluloseproduct.

Owing to the greatly reduced degree of crystallinity and submicronparticle size (0.2-0.5 μm), the LCC products show high enthalpy ofimmersion (LCPC:-31.01 cal/g; LCBC:-19.66 cal/g) and large surface area(LCPC: 2.45 m² /g; LCBC: 2.33 m² /g). Avicel®PH-101 (FMC Corporation),the most commonly and widely used microcrystalline cellulose product,has a surface area of only 1.40 m² /g and shows an enthalpy of immersionvalue of only -16.74 cal/g. LCPC shows strong bonding/binding propertieson compression, and plastic deformations with a lower mean yieldpressure upon compression (82 MPa versus. 125 MPa for Avicel®PH-101),which explains its superiority as a binder in tablets. The LCBC servesas an excellent disintegrate in tablets because of its capillarystructure, that allows for rapid penetration for water, for waterinteractions. Other factors contributing to its superior disintegratingproperties include a lack of entanglement or interlocking between beadparticles, the release of stored elastic mechanical energy as thecompressed but intact beads expand as the tablets disintegrate, thestrong affinity of bead particles for interactions with water, and therelease of high heat of immersion.

LCHC can be used as a novel film forming system, and/or as a bodyingagent or as a carrier or co-carrier for a wide range of bioactivecompounds or cosmetic compounds in systems for application to skin orhair, thereby producing substantive, controlled and/or sustained-releasetopical and transdermal formulations that have superior cosmetic andelegance features. Such formulations may be devoid of fats, waxes, oils,or surfactants, thereby producing natural, hypoallergenic andnon-irritating topical systems. The present LCHC material can also carrybioactive materials to plant surfaces, again producing substantive,biocompatible, controlled and/or sustained release systems, which havethe added advantage of being ultimately biodegradable in theenvironment.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a scanning electron micrograph of low-crystallinity powderedcellulose (LCPC) of this invention.

FIG. 2 is a scanning electron micrograph of low-crystallinity beadcellulose (LCBC) of this invention.

FIG. 3 is a graph showing yield of the low-crystalline cellulose (LCC)product yield in comparison with reaction time at 50° C.

FIG. 4 is a graph showing degree of polymerization of LCC with anincrease in reaction time at 50° C.

FIG. 5 is an x-ray powder diffraction pattern of LCC and for comparisonpurposes of a prior art hydroxycellulose product.

FIG. 6 is a plot showing the crystallinity of LCC increased with anincrease in reaction time at 50° C.

FIG. 7 is a plot showing the inverse relationship between degree ofpolymerization and LCC crystallinity.

FIGS. 8 and 9 show the effects of swelling time at room temperature onthe degree of polymerization of LCC products.

FIG. 10 compares the heat of immersion of LCC product and a conventionalproduct.

FIG. 11 shows the moisture sorption isotherm of low crystalline powderedcellulose (LCPC) against water vapor pressure.

FIG. 12 shows the thickness of tablets prepared at different compressionpressures for tablets using LCBC of this invention and other materialsshowing LCBC tablets show the least reduction.

FIG. 13 shows a scanning electron micrograph of the LCBC tablet with13(a) showing the surface and 13(b) a cross section of the tablet.

FIGS. 14, 15A and 15B show comparisons scanning electron micrographs ofLCPC and Avicel®PH-101 tablets for comparison with FIG. 13.

FIG. 16 compares crushing strengths of LCPC, LCBC, Avicel®PH-101 andlactose tablets, indicating superior binding properties of LCPC.

FIG. 17 shows Heckel plot analysis of LCPC compared to Avicel®PH-101,again demonstrating superior binding properties of LCPC.

FIGS. 18 and 19 show the effect of crystallinity and degree ofpolymerization on the crushing strengths.

FIG. 20 shows that as the degree of polymerization increases thecrystallinity of LCPC first decreases and then increases.

FIG. 21 shows the effect of the degree of crystallinity on the waterpenetration rate.

DETAILED DESCRIPTION OF THE INVENTION

According to the invention, the new low crystallinity cellulose product,readily convertible into powder, bead and hydrated forms, is prepared byreacting a cellulose material with 80% or higher, preferably 85% orhigher, weight percentage phosphoric acid, first at room temperature(i.e. 15° C. to 20° C.) for about an hour, and then at a temperature of45°-75° C., preferably 50°-60° C., for about 2 to 10.5 hours, preferablyabout 3-6 hours. It is important that the phosphoric acid be present ina sufficient quantity to initially uniformly impregnate the cellulosematerial, and that the reaction temperature sequence be observed.Although the minimum weight-to-volume ration of cellulose to phosphoricacid that can be used is about 1:2, it is preferred, for the purpose ofthis invention, to employ a ratio of 1:2-1:20 most preferably 1:3 to1:10. The higher ratios (i.e., higher than 1:10) of cotton linters tophosphoric acid can also be used, but are wasteful of acid and henceless cost effective. The proper treatment of cellulose with phosphoricacid at room temperature causes uniform swelling of the cellulose. As aresult, the crystallinity of the cellulose is largely destroyed. At50°-60° C., the cellulose rapidly hydrolyzes, and consequently,dissolves in the acid to give a viscous solution. The viscosity of thereaction solution decreases as the hydrolysis of the celluloseprogresses.

The decrystallization/depolymerization of cellulose can be performed atroom temperature, but the depolymerization reaction is very slow and cantake several days to produce the desired low crystallinity celluloseproduct with the desired degree of reduced polymerization. If thereaction between cellulose and phosphoric acid is performed at 50°-60°C., without an initial one hour treatment at room temperature, theproduct is a highly crystalline product.

The low crystallinity cellulose dissolved in the acid can be suitablyseparated by combining the reaction mixture under high shear mixing withwater or an organic solvent which is miscible with phosphoric acid, butwhich does not dissolve LCC (e.g., acetone, methanol, and ethanol).Water solvent mixtures may also be used. Filtration, followed by washingthe white solid with water to a near neutral pH, provides a hydrated LCCcake. If desired, the neutralization of the acid, associated with thesolid, can also be suitably effected by washing initially with anaqueous base such as aqueous alkali metal hydroxide or ammoniumhydroxide, followed by water to remove the residual base from the solid.The filtration of the LCC solid can be readily performed using any ofthe conventional separation techniques, such as vacuum filtration,decantation, and centrifugation.

The aqueous colloidal dispersion of LCC is prepared by suspending andhomogenizing the hydrated LCC cake in water. A high-shear mixer or ahomogenizer or a household blender can be used. The LCHC dispersionscontaining 10% or higher weight percentage LCC contents are creams toheavy pastes, whereas those with more than 3% and less than 10% LCC arelotion-like in consistency. The viscosities of the lotion-typedispersions increase with an increase in the LCC content. Alldispersions containing less than 3% LCC settle during storage. Suchdispersions, however, can be readily stabilized by adding minor, buteffective amounts of a water soluble viscosity imparting agent such as,carboxymethylcellulose, methyl cellulose, hydroxypropylcellulose,hydroxypropylmethylcellulose, polyvinylpyrrolidone, cross-linked acrylicacid polymers (Carbopol®Resins), and the like. A water insolublesuspending agent such as bentonite, fumed silicas, modified clays(Thixogel), or the like, can also be used. LCHC also forms stabledispersions in hydroalcoholic mixtures, in water miscible solvents e.g.ethanol, methanol, isopropanol, acetone or a mixed water solvent.

Irrespective of the amount of LCC present, these dispersions formextremely adhesive white films on human skin and hair and on a varietyof other surfaces (e.g., glasses, metals, and woods). If desired, minorbut effective amounts of an appropriate plasticizer such as glycerin,propylene glycol, mineral oil, citric acid esters,N,N-m-diethyltoluamide, diethyl phthalate, dibutyl sebacate, and thelike, can be added to the LCC dispersions. When plasticized, thesedispersions form transparent, flexible, non-tacky, and non-oily films.

The aqueous colloidal dispersions of LCC are microbiologically stable atroom temperature for many months. It is, however, preferred to add minorbut effective amounts of one or more of the commonly used preservativessuch as the phenols, benzoates, parabens, quats (quaternium-15) and thelike, to increase resistance and inhibition of any microbial growth.

The preparation of LCPC is achieved by dehydrating the LCC cake with ananhydrous organic solvent, such as acetone, methyl alcohol,iso-propanol, n-butanol, and the like, followed by drying at roomtemperature or at 50°-80° C., preferably at 70°-75° C. During drying,LCPC converts into a loose agglomerate powder, which can be ground to adesired particle size. If desired, the LCPC can also be prepared byfreeze drying the wet LCC cake, or by milling spray dried materials.

The LCBC is prepared by spray drying an aqueous colloidal dispersion ofLCC. The suitable concentration range of the LCC dispersions, for spraydrying, is from about 1% to 8%, preferably about 3-6%. The size of theprimary particles of LCBC ranges between 0.2 μm and about 1.0 μm, butmost of the particles are about 0.5 μm or smaller. The particle size ofthe LCBC agglomerate, however, ranges from 5 to 250 μm (FIG. 2), but atypical product may have about 90% or more of its particles in a sizesmaller than 45 μm. Dispersions containing higher than 8% LCC do nothave adequate flow and atomization properties, owing to their highlyviscous nature, and are, therefore, not suitable for spray drying.

The yield of LCC ranges from 60% to 90%. As shown in FIG. 3, itdecreases with an increase in the reaction time at 50°-60° C. A scanningelectron micrograph of LCPC, prepared by dehydration of an LCC cake withiso-propanol, followed by drying at 75° C., is shown in FIG. 1, whilethat of an LCBC is reproduced in FIG. 2. The LCPC appears as anagglomerated powder consisting of primary spherical particles of about0.5 μm size, whereas the LCBC agglomerates are spherical in shapecomprising several primary particles of 0.2 to 0.5 μm size.

The degree of polymerization of LCC decreases with an increase in thereaction duration at 50°-60° C., as shown in FIG. 4. It ranges from 35to 180, preferably 80 to 135. The linear relationship between thereaction time and the logarithm of the degree of polymerization valuesindicates that the depolymerization of cellulose by phosphoric acid,under the conditions of this invention, is a first-order reaction, witha rate constant value of 0.314 hour⁻¹. The first-order rate constant forthe depolymerization of cellulose at room temperature is 4.79×10⁻³hour⁻¹.

The x-ray powder diffraction pattern of LCC is shown in FIG. 5. Alsoincluded in the figure are the powder diffractograms of a hydrocelluloseproduct (prepared according to the method provided in U.S. Pat. No.3,146,170), employed as a 100% crystalline standard, and ofAvicel®PH-101. Except for an additional line at 7.4A, the diffractionpattern of LCC is very similar to those displayed by the Avicel®PH-101and the hydrocellulose samples. Based on the integration of alldiffraction peaks (i.e., the total area under the peaks), the degrees ofcrystallinity for LCC and Avicet®PH-101 are 15% and 81% respectively.

The crystallinity of the LCC increases with an increase in the reactiontime at 50°-60° C., as shown in FIG. 6. By way of explanation, and notwishing to be limited thereby, as noted above, the degree ofpolymerization of the product decreases with an increase in the reactiontime. This causes an increase in the particle's surface area. The largerthe surface area, the greater the interaction between particles(cellulose chains), and consequently, the higher the crystallinity. Thisinverse relationship between degree of polymerization and crystallinityof LCC products is shown in FIG. 7. It must be noted that thecrystallinity of microcrystalline cellulose increases with an increasein the degree of polymerization. Thus, in this invention, where asimultaneous low degree of polymerization and low degree ofcrystallinity are sought, very precise control of reaction times andtemperatures are required.

In FIGS. 8 and 9, the effects of swelling time (i.e., duration of acidtreatment at room temperature) on the degree of polymerization andcrystallinity of LCC products, are compared. The results show nosignificant changes in the two properties when the reaction duration, atroom temperature, is increased from one hour to fourteen hours. Thesefindings, and the fact that the direct treatment of cellulose withphosphoric at 50°-60° C., without an initial treatment at roomtemperature, produces a highly crystalline product, suggest that aninitial swelling period of about one hour or less at room temperature,is critical to the preparation of LCC.

Compared to LCPC, LCBC shows a slightly higher degree of crystallinity.This, probably, occurs due to the recrystallization of LCC, to a smallextent, in water, during spray drying.

The mean specific surface areas of LCPC and LCBC particles are 2.45 m²/g and 2.33 m² /g, respectively. The small difference in specific areabetween the powder and bead materials confirms that the primaryparticles comprising the beads are loosely associated, and hence loselittle of their effective surface area. LCBC shows a higher bulk densityand lower porosity compared to LCPC. The bulk densities for the LCBC andLCPC are 0.85 g/cm³ and 0.431 g/cm³, and the porosity values are 49.1%and 72.7%, respectively. This difference in the bulk densities andporosities of the two products are due to the differences in theparticle's shapes. The LCBC particles, as shown in FIG. 2, are highlyspherical in shape, which facilitates a more tightly packed powder bed,whereas LCPC is a highly agglomerated powder composed of irregular-shapeparticles, which, when packed, has more void spaces as a result ofentanglement or interlocking of particles. The densities and porositiesof the LCPC and LCBC compacts, prepared by compressing 0.5 grams of theLCPC and LCBC each at 3000 lb for 30 seconds, are 1.381 g/cm³ and 1.241g/cm³ and 21.4% and 12.6%, respectively. The density values suggest alarger volume reduction for the LCPC compact than for the LCBC compact.This occurs because the LCBC particles retain their integrity, to alarge extent, under compression, whereas the LCPC particles undergosignificant plastic flow, thereby filling void spaces and forming newbonds on the true contact areas.

Calorimetric methods have been widely used to study the heat of wettingor other properties of water insoluble excipients such as interactionsbetween additives. Calorimetry measures a progressing change of anextensive property, enthalpy, as one physical state is changing toanother state. The enthalpy of immersion, (ΔH_(i)), is the heat ofimmersion of the solid, representing energy changes due to wetting,hydration, swelling, surface changes, or the release of stored energy ofsolids in water. Thus, cellulose excipients having different levels ofcrystallinity would be expected to show different enthalpies ofimmersion. FIG. 10 compares the heat of immersion of various LCCproducts, provided by this invention, and Avicel®PH-101 having a percentof crystallinity of 80%. The negative ΔH_(i) values obtained indicatethat the interaction between cellulose and water is an exothermicreaction. The -ΔH_(i) increases with a decrease in the crystallinity ofthe cellulose. This is because as the crystallinity decreases morehydroxyl groups become available for interactions with water, andconsequently, the ΔH_(i) increases. The ΔH_(i) values for the LCPC andLCBC products, having 27% crystallinity, are -31.01 cal/g and -19.66cal/g, respectively, whereas the corresponding value for theAvicel®PH-101 is -16.74 cal/g. When LCBC is compressed at a pressure of3000 lb for 30 seconds, the ΔH_(i) is increased by 9.8%. This increasein the ΔH_(i) value on compression is due to the increased defectstructure, and release of elastic energy stored in the LCBC compact as aresult of compression. The ΔH_(i) of the LCC is also dependent on themoisture content present, increasing with a decrease in the moistureamount. For example, the ΔH_(i) values for LCPC containing 5% and 0%moisture are 24.72±0.53% cal/g and 31.02±1.92 cal/g, respectively.

The heat of wetting, ΔH_(w), of LCC, calculated from ΔH_(i) using Hess'sLaw, is -6.9 cal/g, about 27.1% higher than that reported forAvicel®PH-101 (R. G. Hollenbeck, G. E. Peck, and D. O. Kildsig, J.Pharm. Sci., 67, 1599 (1978)). The moisture sorption isotherm of LCPCagainst water vapor pressure is shown in FIG. 11. The moisture contentincreases with an increase in the water vapor pressure.

The preparations of LCC, LCPC, LCBC, and LCHC and their applications inthe formulation of a variety of pharmaceutical, cosmetic, and personalcare products are illustrated by the following examples, which are notto be construed as limiting.

EXAMPLE 1 Decrystallization/depolymerization of Cellulose UsingPhosphoric Acid

One thousand milliliters of 85-86% phosphoric acid was placed in anappropriate size flat-bottom glass or polyvinylidine fluoride container.To this was added 100 grams of cotton linter sheet, broken into smallpieces, or cotton linter fluff. The thoroughly wettedcellulosephosphoric mixture was then allowed to stand at roomtemperature for about one hour. The reaction container was then placedin a water-bath that had been adjusted to 50°-60° C. After about one andone half to two hours of heating, the reaction mixture was stirred usinga mechanical stirrer equipped with an acid-resistant propeller and ashaft. Mixing and heating were continued until a light cream coloredsolution was formed (about 2-3 hours). The reaction solution wasimmediately poured into water with vigorous stirring. The water volumecan be about five-to-ten times that of the acid volume. An immediateprecipitation of white solid occurred. The solid was then filtered usinga buchner funnel and a Whatman Grade-113 filter paper. An extensivewashing of the solid with water followed, to a near neutral pH of thewash water, to produce a hydrated low crystallinity cellulose (LCHC),with an 85-90% yield (based on the dried weight basis). If desired, thewhite solid residue can be washed first with an aqueous solution of abase, such as sodium or potassium hydroxide or ammonium hydroxide, andthen with water to remove the inorganic phosphates.!

EXAMPLE 2 Preparation of Low Crystallinity Powder Cellulose (LCPC)

The hydrated white cake, prepared according to the procedure of Example1, was dispersed in an appropriate volume of methanol, ethanol, acetone,or iso-propanol. The mixture was stirred with a mechanical stirrer forabout 15 minutes, or until a uniform dispersion was formed and thenfiltered. This process was repeated three-to-five times to ensurecomplete depletion of water from the cellulose. The dehydrated lowcrystallinity cellulose residue was then broken into small lumps with aspatula, and dried either at room temperature overnight or at 75° C. for4-6 hours. Following drying, the low crystallinity cellulose powder wasground with a mortar and pestle or using a pulverizing blender, toreduce the particle size of the agglomerates to below 125 μm.

EXAMPLE 3 Preparation of Low Crystallinity Bead Cellulose (LCBC)

The low crystallinity hydrated cellulose, prepared according to theprocedure of Example 1, was homogenized in an appropriate amount ofdistilled purified water, to give an LCC concentration of about 4-8%.The resulting homogeneous colloidal dispersion was then spray dried,using a Nitro Utility Spray Dryer (Nitro Atomizer, Ltd., Columbia, Md.,USA), equipped with a 12 cm diameter radial vane centrifugal atomizer,operating at 24,000 rpm and an inlet temperature of about 200±5, and anoutlet temperature of 100±3. The low crystallinity bead cellulosepowder, thus obtained, was collected, and passed through a #120(125 mm)sieve.

EXAMPLE 4 Comparative Evaluation of LCPC and LCBC as Direct CompressionExcipients in Tablets

A. As Binders

0.5 grams of LCPC and LCBC, prepared according to the procedures ofExamples 1-3, were separately compressed for 20 seconds, without alubricant, into cylindrical flat-face tablets at different compressionloads using the same punch (flat-faced) and die (11 mm diameter).Tablets of Avicel®PH-101 and lactose, employed for comparison purposes,were also prepared in the same manner. The results obtained arediscussed below:

The thickness of the tablets prepared at different compression pressuresis depicted in FIG. 12. LCBC tablets show the least volume reduction,whereas Avicel®PH-101 and LCPC tablets exhibit the highest. The lactosetablets show smaller volume reduction, compared to the LCPC tablets (andAvicel®PH-101), but higher than for the LCBC tablets. The lowcompressibility of the LCBC material is attributed to its inability toundergo plastic flow, under compression. This is reflected in thescanning electron micrograph (of the LCBC tablet) depicted in FIG. 13,which shows a deformed compressed bead structure (FIG. 13b), with largevoid spaces (FIG. 13a), and definite boundaries between the particles.In comparison, the scanning electron micrographs of LCPC andAvicel®PH-101 tablets (FIGS. 14 and 15) demonstrate strong interactionsbetween the primary particles, with disappearance of some boundaries,especially in regions near the edges of the tablet. This accounts forthe higher compressibility of these materials. The smaller thickness ofthe lactose tablets, compared to the LCBC tablets, is due to thefragmentation of the lactose particles, under compression, which fillthe interparticle spaces to produce a relatively tightly packed compact.

FIG. 16 compares the crushing strengths of LCPC, LCBC, Avicel®PH-101,and lactose tablets. The highest crushing strength values for the LCPCtablets clearly indicate superior binding properties of the LCPCmaterial. The poorer compatibility (i.e. binding properties) of theAvicel®PH-101, compared to LCPC, is due to its higher crystallinity.This is because as the crystallinity increases, a smaller number ofhydroxyl groups become available for interactions. As a result, theweaker tablet is formed. Further support for the superior bindingproperties of the LCPC material, compared to Avicel®PH-101, is providedby Heckel Plot analysis (FIG. 17). The linear portions of the plotsindicate that both LCPC and Avicel®PH-101 undergo plastic flow undercompression. The mean yield pressure values, calculated from the slopesof the linear portions of the curves, are 82 MPa and 125 MPa for theLCPC and Avicel®PH-101, respectively. The lower (mean yield pressure)value for the LCPC indicates that the LCPC material has a greaterability to deform plastically at lower pressure than Avicel®PH-101.Further, LCPC, owing to the agglomeration of primary particles, probablydeforms along many planes, whereas Avicel undergoes plastic deformationalong slip planes only (R. F. Shangraw, in "Pharmaceutical Dosage Forms:Tablets," H. A. Lieberman, L. Lachman, and J. B. Schwartz, eds., MarcelDekker, Inc., New York, 2nd ed., Vol. 1, p. 195-96, 209-216 (1989)).These factors make LCPC more compressible than Avicel®PH-101. Theporosities of the LCPC and Avicel®PH-101 compacts correspond to 12.5%and 15.4%, respectively, further documenting the tighter packing of theLCPC than Avicel®PH-101 under compression.

LCBC tablets are stronger than lactose tablets. This is because LCBC,owing to its low crystallinity and submicron particle size, demonstratesmore extensive hydrogen bonding. In comparison, lactose forms bonds onlyin the glassy region which constitutes a very small portion of thelactose crystals.

The results of viscoelastic analysis, which provides the energy changein the unloading phase of the tabletting process, including the work dueto the elastic deformation and viscous deformation, are presented inTable 1.

                  TABLE 1                                                         ______________________________________                                        Cellulose form                                                                           LCBC       LCPC    AVICEL PH-101                                   ______________________________________                                        Avg. Wt.   0.538      0.543   0.535                                           P(MPa)     153        173     109                                             W.sub.o (J/cm.sup.3)                                                                     -12.30     -13.04  -5.23                                           W.sub.i (J/cm.sup.3).sub.3                                                               9.55       9.00    3.75                                            W.sub.Fdx (J/cm.sup.3)                                                                   -2.73      -3.31   -1.45                                           W.sub.L (J/cm.sup.3)                                                                     30.52      38.92   29.62                                           Increment  7          8       5                                               ______________________________________                                    

The stress P values decease in the order from LCPC to LCBC and to AVICELPH-101. Both LCPC and LCBC show higher negative values for the work dueto elastic deformation than AVICEL PH-101. This is due to the submicronparticle size of the LCPC and LCBC which provides larger surface areafor interactions, and consequently, requires more work for the elasticdeformation. AVICEL PH-101 shows extensive interlocking of the fibers,and thereby demonstrates a lower value of the work of elasticdeformation. The higher W_(i) values for the LCPC and LCBC, compared toAVICEL PH-101, suggest that the LCC primary particles undergo a greaterextent of viscous flow in the unloading phase of the tabletting process.This results in an increase in the contact area, which facilitatesstronger interactions to consolidate the tablet while dissipating theexcess energy in the forms of heat and entropy. The higher negativeforce displacement work values for the LCPC and LCBC, compared to AVICELPH-101, are due the absence of any interlocking of primary particles inthe LCPC and LCBC aggregates. There is no difference in the loading workamong the LCPC, LCBC, and AVICEL PH-101. The incremental values, whichreflect the extent of expansion in the unloading phase, are consistentwith the work values due to elastic deformation. The viscoelasticanalysis further documents the superiority of LCPC and LCBC materials asto tablet excipients, compared to microcrystalline cellulose.

The effects of crystallinity and degree of polymerization on thecrushing strengths of the LCPC tablets are depicted in FIGS. 18 and 19.Tablets for this study were prepared by compressing 0.5 grams of LCPC,having different crystallinity and degree of polymerization values, at3000 lb for 20 seconds. As shown in FIG. 18, the crushing strengths ofthe tablets increased from 20 Kg to 100 Kg when the crystallinity of theLCC decreased from 45% to 12%. This shows that as the crystallinitydecreases, stronger tablets are formed, as would be expected. FIG. 19shows that the crushing strength of the LCPC tablet first increases thendecreases with an increase in the degree of polymerization. This isbecause as the degree of polymerization increases the crystallinity ofLCPC first decreases and then increases, as shown in FIG. 20.

The effect of the particle size on the fluidity of the LCPC compared toa like particle size AVICEL PH-101 powder and on the crushing strengthis compared in Table 2.

                  TABLE 2                                                         ______________________________________                                        Cellulose Particle size                                                                             Flow rate Crushing Strength                             form      (μm)     g/sec     Kg                                            ______________________________________                                        LCPC      50          1.75 ± 0.31                                                                          74.8 ± 2.9                                 LCPC      125-350     5.61 ± 0.91                                                                          76.2 ± 1.4                                 AVICEL PH-101                                                                           50          1.30 ± 0.34                                                                          58.4 ± 1.8                                 ______________________________________                                    

Generally, the larger the particle size of a powder, the better thefluidity or powder flow. However, the crushing strength of plasticmaterials has been shown to decrease with an increase in particle size(M. Sheik-Salem and J. T. Fell, Acta Pharm. Suec., 19, 391 (1982); A. H.DeBoer et al., Pharm. Weekblad, Sci. Ed., 8, 145 (1986); N. R. Anderson,G. S. Banker, and G. E. Peck, J. Pharm. Sci., 71, 7 (1982)). Thus, theloss of crushing strength, accompanying an increase of particle size, isof general concern in tablet making although larger particlescharacteristically provide much better powder flow. The data listed inTable 2 indicate that LCPC, irrespective of particle size and flow rate,provide tablets with nearly the same crushing strength values. Thesignificance of this unique property of LCPC is that the preparation ofLCPC with a larger particle size, that demonstrates excellent powderflow, at the same time, produces compacts with the same strong cohesionproperties as the fine particles. Both adequate powder flow and strongcompact cohesion properties are desirable features in excipients used intablet production. The reason that LCPC possesses this unique property,among tablet excipients, is that the LCPC particles are actuallyagglomerates, each made up of hundreds to thousands of individualcolloidal particles.

B. As Disintegrants

Tablets of LCPC, LCBC, and AVICEL PH-101, each weighing 0.5 grams, wereprepared using a Carver press at either 1000 lb for 20 seconds or at3000 lb for 30 seconds. The heats of immersion, water penetration rateand the disintegration time of the tablets are presented in Table 3.

                  TABLE 3                                                         ______________________________________                                                   Water                  Heat                                                   Penetration Disintegration                                                                           of Immersion                                Sample     Rate (mg/sec)                                                                             Time       .increment..sup.H.sub.i                     ______________________________________                                        LCBC       3.347       5.0 seconds                                                                              -21.59                                      LCPC       0.0         --         not detd.                                   AVICEL PH-101                                                                            1.724       >1 hour    -13.63                                      ______________________________________                                    

The water penetration data show that water penetrates much more rapidlyin the LCBC tablets than in AVICEL PH-101 tablets. The LCPC tablets didnot show any appreciable penetration of water. The greater waterpenetration rate of the LCBC tablets is due to its capillary structure(FIGS. 2 and 12) and reduced degree of crystallinity. LCPC, though alsohaving a reduced degree of crystallinity, undergoes high plastic flowunder compression, causing the primary particles to pack themselves verytightly (see FIG. 14). The penetration of water in the AVICEL tabletoccurs through the void spaces produced as a result of entanglement orinterlocking of primary particles during compression (see FIG. 15):

The effect of the degree of crystallinity on the water penetration rateis depicted in FIG. 21. As is evident from the Figure, the waterpenetration increases with a decrease in the crystallinity, because moreand more free hydroxyl groups become available for interactions.

The rapid disintegration of the LCBC tablet compared to the AVICELPH-101 tablet is due to its greater capillary action. Other factors thatcontribute to its superior disintegrating properties include the lack ofentanglement of primary particles, release of stored mechanical(elastic) energy as the tablet disintegrates, stronger affinity forinteraction with water, and the release of a higher heat of immersion.

EXAMPLE 5 Comparative Evaluation of LCPC and AVICEL PH-101 as Binders inAcetaminophen Tablets

Test tablets were prepared by thoroughly mixing 320 mg of acetaminophen,a poorly compressible material, with 175 mg of LCPC or AVICEL PH-101,and 5 mg of magnesium stearate, followed by compression at a pressure of3000 lb for 20 seconds using a Carver press. A commercial acetaminophentablet, Tylenol®, having the same tablet size and drug content, was alsotested for comparison. The results are presented in Table 4.

                  TABLE 4                                                         ______________________________________                                        Tablet       Disintegration Time                                                                          Crushing Strength                                 Type         (min)          (Kg)                                              ______________________________________                                        LCPC         11.4 ± 0.2  9.00 ± 1.14                                    AVICEL PH-101                                                                              14.6 ± 2.1  6.53 ± 0.40                                    Tylenol      0.68 ± 0.03 8.70 ± 0.03                                    ______________________________________                                    

The higher crushing strength of the LCPC-acetaminophen tablets comparedto the AVICEL PH-101 tablets is consistent with the superior cohesionproperties of the LCPC. The LCPC-acetaminophen also disintegrates fasterthan the AVICEL tablet (11.4 min. vs. 14.6 min.). This is due to thestronger affinity of the LCC material with water. Compared to LCPC andAVICEL-acetaminophen tablets, the Tylenol® tablet disintegrates veryrapidly, and shows an intermediate crushing strength value.

The strong cohesion properties of the LCPC, coupled with its excellentflow properties and effectiveness as a disintegrant in drug mixturesystems, demonstrate the unique usefulness and superiority of LCPC as adirect compression combined binder/disintegrant/diluent excipientmaterial in tablet making.

EXAMPLE 6 Disintegration of LCBC-Griseofulvin Tablets

LCBC-Griseofulvin tablets, comprised of 215 grams of LCBC and 250 gramsof griseofulvin, were prepared in the same manner as described inExample 6. The disintegration time and the crushing strength values ofthe tablets are listed in Table 5. Fulvicin U/F, a commercialgriseofulvin tablet containing the same amount of drug and of the samesize as the test tablet, was employed as a reference.

                  TABLE 5                                                         ______________________________________                                        Tablet       Disintegration Time                                                                          Crushing Strength                                 Type         (min)          (Kg)                                              ______________________________________                                        LCBC         0.88 ± 0.15 23.8 ± 0.61                                    Fulvicin U/F 1.48 ± 0.18 11.6 ± 0.93                                    ______________________________________                                    

The LCBC-griseofulvin tablet demonstrated a faster disintegration time(0.88 minutes versus 1.48 minutes) and a stronger crushing strength(23.8 Kg versus 11.6 Kg) than the commercial griseofulvin tablet.

EXAMPLE 7 Preparation of Cream, Lotion and Spray Formulations Using LCHC

Owing to its high suspendibility in water and hydroalcoholic solventsystems and its ability to form extremely adhesive films on the skin.LCHC can be used to prepare a wide range of pharmaceutical (topical andtransdermal), cosmetic, agricultural, and like products. Conventionalformulation procedures can be used to prepare cream, lotion, and sprayproducts, utilizing the present LCHC material. For example, variousformulation ingredients (i.e., viscosity enhancing agents, plasticizers,preservatives, active drugs, etc.) can be simply mixed with the LCHCdispersion using a mechanical stirrer, followed by homogenization of themixture. If desired, heated oil and water phases can be preparedseparately, combined, and the resultant blend allowed to cool to roomtemperature with constant agitation. Formulations, prepared utilizingthe present LCHC material, rub-in smoothly on the skin, and rapidly dryto form Uniform, transparent, invisible, flexible, and non-tacky andnon-oily films.

Active ingredients can be selected from a wide variety of cosmetics,pharmaceuticals, insecticides, herbicides, rodenticides, fungicides,pigments, insect repellents or fragrances.

The following examples are provided to more fully illustrate the utilityof the LCHC material in topical formulations, and should not beconstrued as limiting the scope thereof.

A. Antihistamine/Skin Protectant Lotion

The procedure of Example 1 was repeated to produce an LCHC cake thatcontained 15% LCC. 24.1 grams of this cake was taken in 15 grams ofwater, and then thoroughly mixed with 5.0 grams of diphenhydraminehydrochloride, and 0.5 grams of glycerin. The mixture was thenhomogenized to produce a white stable lotion product. This productrubs-in smoothly on the skin, and can be used for relief from itchingdue to minor skin irritations.

B. Anti-acne Lotion and Cream

An LCHC cake containing 12.4% of LCC was prepared according to theprocedure of Example 1. To 28.3 grams of this cake, equivalent to about3.5 grams of the LCC, was added about 43.7 grams of water. The mixturewas stirred until a homogeneous suspension was formed. While continuingstirring, 0.3 grams of the cross-linked polyacrylic acid (Carbomer 934P,Goodrich), 0.15 grams of methyl paraben, and 0.10 grams of propylparaben, were added to the LCHC mixture. Once the Carbomer wascompletely dissolved, 14.3 grams of 30% benzoyl peroxide U.S.P. wasadded. The mixture was then homogenized to produce a homogeneousdispersion. At this stage, while continuing stirring, 13.0 grams ofglycerin was added to the mixture. After stirring the mixture for aboutan hour, 0.3. grams of triethanolamine was added. An immediate increasein the viscosity occurred. The lotion product, thus obtained, wasstirred for an additional one to one and a half hour, and thenhomogenized. The product is cosmetically superior and elegant. Being100% water based, the product, when applied on the skin, rapidly driesto form uniform, transparent, virtually invisible and non-oily films.The oil-based systems tend to aggravate acne conditions.

A cream product, exhibiting similar cosmetic elegancy andcharacteristics as were observed with the lotion product, was preparedusing the same procedure as described above. The compositions of thevarious ingredients were: LCHC 32.0 grams (corresponded to 5.0% LCC),Carbomer 934P 0.5 grams, triethanolamine 0.5 grams, methyl paraben 0.15grams, propyl paraben 0.10 grams, benzoyl peroxide 14.3 grams, glycerin14.0 grams, and water to 100 grams.

C. Anti-inflammatory Cream

48.1 grams of the LCHC cake (equivalent to about 7.5 grams of the LCC),0.5 grams of the Carbomer 934P, 0.15 grams of methyl paraben, and 0.10grams of propyl paraben were combined with 39.6 grams of water. Themixture was stirred to produce a homogeneous dispersion. 10.0 grams ofglycerin and 1.0 grams of hydrocortisone were then added to the mixturewith stirring. Further stirring for an additional hour, followed byhomogenization produced a 1% hydrocortisone cream product.

D. External Analgesic Cream

A mixture containing 22.4 grams of LCHC cake (equivalent to 3.5 grams ofthe LCC), 1.0 grams of Tween 20, 0.25 grams of Carbomer 934P, 0.15 gramsof methyl paraben, 0.10 grams of propyl paraben, and 25.6 grams water,was stirred until a homogeneous dispersion was formed. To this, whilecontinuing stirring, a solution that comprised 10.0 grams of menthol and30.0 grams of methyl salicylate, was added. To the resulting mixturewere then added 10.0 grams of glycerin, 0.25 grams of triethanolamine,and 0.25 grams of hydroxypropylmethylcellulose (Methocel®Krm, DowChemicals), in the order written. The resulting cream product wasstirred for an additional hour and then homogenized. It was stored in ahalf or one ounce aluminum tube that had a lining of a phenolic epoxypolymer. The product is physically and chemically stable, and rubs-insmoothly on the skin to produce a monolithic non-greasy film havingprolonged release characteristics.

E. Spray System for Perfumes

A cosmetically elegant spray formulation was prepared by homogenizing adispersion that comprised 22.4 grams of LCHC cake (equivalent to 3.0grams of LCC), 0.15 grams of methyl paraben, 0.10 grams of propylparaben, 0.5 grams of Tween 20, 0.1 grams of Carbomer 934P, 0.1 grams oftriethanolamine, 10.0 grams of glycerin, and 1.0 to 3.0 grams or more ofa perfume. The product can be sprayed utilizing a standard pump spraypackage assembly.

What is claimed is:
 1. A low crystallinity powdered cellulosic materialhaving a degree of polymerization within the range of 35 to 180 and adegree of crystallinity within the range of 15% to 45% derived fromdehydrating a low crystallinity cellulosic cake material prepared byreacting cellulosic material with 85%-99% concentrated phosphoric acidin a sequential temperature reaction with a first sequential step beingat a temperature within the range of 15° C. to 30° C. for up to one hourand a second sequential step being within the range of 45° C. to 75° C.for from about 2.0 hours to about 10.5 hours, with the weight ratio ofcellulose to phosphoric acid being from 1:2 to 1:20 and then separatingthe low crystallinity cellulosic material to provide a cake which isreactivated with an anhydrous organic solvent followed by drying andgrinding to provide a low crystallinity powdered cellulosic materialhaving a particle size of less than 1.00 μm.
 2. A low crystallinitybeaded cellulosic material having a degree of polymerization within therange of 35 to 180 and a degree of crystallinity within the range of 15%to 45% prepared from reacting a cellulosic material with 85%-99%concentrated phosphoric acid in a sequential temperature reaction with afirst sequential step being at a temperature within the range of 15° C.to 30° C. for up to one hour and a second sequential step being withinthe range of 45° C. to 75° C. for from about 2.0 hours to about 10.5hours, with the weight ratio of cellulose to phosphoric acid being from1:2 to 1:20 to provide a low crystallinity cellulosic product whereinthe particles have a size of less than 1.00 μm which is then separated,water dispersed, and then spray dried.
 3. The product of claim 2 whichis prepared using a colloidal dispersion that contains from about 1% toabout 8% concentration of low crystallinity cellulosic material.
 4. Theproduct of claim 2 which is prepared using a colloidal dispersion thatcontains from about 3% to about 6% by weight concentration ofcolloidally dispersed low crystallinity cellulosic material.
 5. Theproduct of claim 2 which has a primary particle size for the majority ofsaid particles of from 0.2 μm to about 0.5 μm.
 6. The product of claim 5wherein the particles are spherical.
 7. A formulary product selectedfrom the group consisting of pharmaceutic products, cosmetic products,veterinary products, agricultural products and personal care productscomprising:a product active and as an excipient-effective amount of lowcrystallinity cellulosic material having a degree of polymerizationwithin the range of 35 to 180 and a degree of crystallinity within therange of 15% to 45% obtained by reacting said cellulosic material withinthe range of 15° C. to 30° C. for up to one hour and a second sequentialstep being within the range of 45° C. to 75° C. for from about 2.0 hoursto about 10.5 hours with 85% to 99% concentrated phosphoric acid in asequential temperature reaction to provide particles of a size less than1.00 μm.
 8. The product of claim 7 wherein the formulary product is apharmaceutic product.
 9. The product of claim 7 when the formularyproduct is a cosmetic product.
 10. The product of claim 7 wherein theformulary product is a personal care product.